Recently, Claris Lifescience Ltd., a maker of injectable pharmaceuticals in India, received a warning letter from the FDA that no firm wants to see:
“…Your firm received a complaint from a U.S. distributor (Sagent Pharmaceuticals) informing you that Metronidazole Injection USP IV bags (lot A090744) were contaminated with a swirling mass, which the complainant identified as the fungus Cladosporium species.”
The FDA then informed Claris that it had not adequately investigated the root cause of the contamination, nor had it thoroughly reviewed its manufacturing and quality control processes.
These letters—and the problems that cause them—plague drug manufacturers far too often. They are usually the result of, among other things, not having a validated environmental monitoring program in place to ensure quality and purity of the product. And while prevention of environmental contaminants is a key concern of any drug manufacturer, this issue affects makers of injectables more immediately than makers of other pharma products, because sterile drugs are susceptible to particulates, pyrogenic, and microbiological contamination. Also, there is nothing between an injectable product and human blood, brain and organ.
Environmental contamination can come from a number of sources, the most important of which is human handling and processing the drug product or its ingredients. It is estimated that over 80% of the contamination comes from the human element. Introduction of microbial enzymes, changes in impurity profiles, and increases in bacterial endotoxin levels can increase product variability at the least, and cause severe adverse effects including death at worst. A failure in the environmental safeguards set up to prevent these problems means that your batch has to be destroyed, and an investigation has to determine the cause of this failure before the next batch run begins.
However, if the product has already shipped from your facility, then it has to be recalled. In the event of a recall, you are required to notify the FDA, and the FDA then makes your recall public. Many drug companies have not survived this ordeal.
Strategies prevent recalls
There are a number of steps you need in your environmental monitoring and quality assurance processes to stay away from FDA warnings:
• Contamination and cross-contamination are tightly linked to a lack of properly documented and validated cleaning processes. Improper labeling of drug ingredients and the lack of effective line clearance processes also rate high on the list of causes for contamination and cross-contamination of products.
• Understand the close ties between the cleaning process validation and product recalls. If your cleaning process isn’t robust and hasn’t been validated properly, then cleaning will not be able to identify contaminations or cross contaminations. Your quality department or processor will identify problems only after the sample has been made and sent to the QC lab for results. Validating your cleaning process has to be done properly, to ensure that there is no contamination.
• Your environmental program design has to meet certain criteria for every class of clean room. Manufacturers need to make sure that personnel gowning is done properly, employees have received proper training and contact plates get tested on a regular basis, after batch processing.
• Re-validate analytical methods whenever there is a change in material suppliers. Changing from a supplier in Spain, for example, to an Italian supplier may sound simple. But many companies overlook the requirement that they have to re-validate the analytical method. It may need to be optimized and requires re-training of the analysts.
• For all these requirements, you’d have to document all your new processes.
Tactics important, but need to fit into big picture
Many in-lab tactics are available from FDA guidance documents and the International Council for Harmonization (ICH). They provide excellent guides for specific steps to take and issues to look out for.
But these steps, while important, will not by themselves prevent an environmentally triggered batch failure and product recall. There’s a much bigger picture, and any successful program must mean that management, line employees, engineers and quality assessment staff must work together with the support of a subject matter expert in the process and evaluate how the whole process works. Corrective and preventive action (CAPA) is very important, but only if it works toward continuous improvement and toward a clearly defined system and goal.
To that end, the concept of design space needs to be integrated into any process assessment, quality control and environmental monitoring program. Design space is the multi-dimensional combination and interaction of input variables and process parameters that have been demonstrated to provide assurance of quality. It is the result of extensive analysis of process parameters to determine appropriate variability of your product, and process steps. Within the regulatory framework, working within the design space submitted in an application is not considered a change. Movement out of the design space is considered to be a change and would normally initiate a regulation post-approval change process, requiring regulatory notification.
This is not easy to set up, but a design space concept properly implemented from development to manufacturing significantly reduces the chance of having a drug product being recalled. At Synergy Bioscience, we have the experts who can review your processes, give the proper technical opinions that will avoid you the time and money wasted as a result of recalls.
How often do you have a product recall in your facility and what have you done about it?
Do you know what you need to do in that event?
Let us know your experience, and feel free to contact us for a deeper conversation.